US4427693A - Antiinflammatory 4,5-diaryl-α,α-bis (polyhalomethyl)-2-thiophenemethanamines - Google Patents
Antiinflammatory 4,5-diaryl-α,α-bis (polyhalomethyl)-2-thiophenemethanamines Download PDFInfo
- Publication number
- US4427693A US4427693A US06/316,661 US31666181A US4427693A US 4427693 A US4427693 A US 4427693A US 31666181 A US31666181 A US 31666181A US 4427693 A US4427693 A US 4427693A
- Authority
- US
- United States
- Prior art keywords
- compound
- sub
- mammal
- antiinflammatory amount
- fphenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
Definitions
- This invention relates to antiinflammatory diaryl thiophenes.
- Inflammation is a disease process characterized by redness, fever, swelling, and pain.
- Arthritis in its various forms, is the most prevalent, chronic, and severe of the inflammatory diseases. Traumatic injury and infection also involve inflammation, and antiinflammatory drugs are often used in their treatment.
- the usefulness of most commercial antiinflammatories is limited because of toxicity and adverse side-effects. Many produce gastric irritation and other effects, such as changes in blood cells and central nervous system. Adreno-cortical steroids produce gastric irritation and suppression of normal adrenal function.
- the present invention results from efforts to develop new antiarthritic compounds with good antiinflammatory activity and minimal side effects that could be more effective in treating arthritis than presently available drugs.
- some compounds of this invention have analgesic activity. This additional property is desirable in treatment of arthritis or related diseases; however, such compounds can be employed solely to alleviate pain.
- This invention relates to novel antiinflammatory compounds of Formula I: ##STR1## where
- X H, F, Cl, Br, NO 2 , C 1 -C 2 alkyl, OR 7 , --N(R 7 ) 2 or R 7 S(O) n ;
- n 0, 1 or 2;
- Y H, F or Cl with the proviso that when Y is F or Cl, then X is F, Cl or H;
- R 5 H or alkyl of 1-3 carbons
- R 6 H or alkyl of 1-3 carbons
- R 7 alkyl of 1-2 carbons
- R 1 and R 2 CF 3 ;
- X F or CH 3 S
- Specifically preferred compounds are:
- the compounds of the invention may be prepared by the following reactions:
- a 2,3-diarylthiophene II is reacted with a strong base such as n-butyl lithium or t-butyl lithium in an aprotic solvent such as tetrahydrofuran, diethyl ether or toluene optionally in the presence of a complexing agent such as tetramethylethylenediamine and then treated with a N-silylated halogenated ketone imine.
- the reaction can be carried out at a temperature from -78° to 110° .
- a 2-bromo-4,5-diarylthiophene III is treated with a strong base such as n-butyl lithium or t-butyl lithium in an aprotic solvent such as tetrahydrofuran, diethyl ether or toluene optionally in the presence of a complexing agent such as tetramethylethylenediamine at a temperature from -78° to 40° , preferably at -30° to 30° C.
- the resultant lithio thiophene is treated with a N-silyated halogenated ketone imine at a temperature from -78° to 110° and then treated with aqueous acid at a temperature from 0° to 100° to give compound Ia.
- 2-Bromo-4,5-diarylthiophenes are prepared by the reaction of a 2,3-diarylthiophene II with bromine (1 equivalent) in a solvent such as methylene chloride, acetic acid or their mixture at a temperature from -20° to 30° .
- a 2,3-diarylthiophene II is reacted with a strong base such as n-butyl lithium or t-butyl lithium in an aprotic solvent such as tetrahydrofuran, diethyl ether or toluene optionally in the presence of a complexing agent such as tetramethylethylenediamine and then treated with a N-alkylated halogenated ketone imine to give compound Ib.
- the reaction can be carried out at a temperature from -78° to 100° C.
- a 2-bromo-4,5-diarylthiophene is treated with a strong base such as n-butyl lithium or t-butyl lithium in an aprotic solvent such as tetrahydrofuran, diethyl ether or toluene optionally in the presence of a complexing agent such as tetramethylethylenediamine at a temperature from -78° to 40° C., preferably at -30° to 30° C.
- the resultant lithio thiophene is treated with a N-alkylated ketone imine at a temperature from -78° to 110° C. to give compound Ib.
- a dibromothiophene of structure IV in an aprotic solvent such as diethyl ether or tetrahydrofuran at a temperature from -78° to 35° C. is metallated with a reagent such as n-butyl lithium or magnesium and then treated with a N-silylated halogenated ketone imine.
- the resultant intermediate is further treated with a reagent such as n-butyl lithium or magnesium and then with an alkylating agent.
- Treatment with aqueous acid at a temperature from 0° to 100° then gives compound Ia.
- 2,3-Dibromo-4,5-diarylthiophenes IV are prepared by reaction of a 2,3-diarylthiophene with bromine (2 equivalents) in a solvent mixture such as methylene chloride and acetic acid at a temperature from 10° to 55°.
- 2,3-Bis(4-methoxyphenyl)thiophene (2.96 g, 10 mmole) was dissolved in 75 ml toluene and the volume reduced by approximately two thirds by distillation.
- the cooled solution was diluted with 100 ml diethyl ether, cooled to 0° and treated with 1.6 M n-butyl lithium (7 ml, 11 mmole).
- the reaction mixture was heated at reflux for 1.5 hours, cooled to 0° and treated dropwise with a solution of N-trimethylsilyl hexafluoroacetone imine (2.8 g, 12 mmole) in 5 ml diethyl ether.
- the reaction mixture was stirred for 4 hours at 0° and then quenched with water.
- the aqueous phase was extracted with ethyl acetate and the combined organics washed with brine, dried and concentrated on the rotary evaporator.
- N-alkylated halogenated ketone imine Using the appropriate N-alkylated halogenated ketone imine, the following compounds can be prepared following the procedures outlined above and illustrated in the preceding example.
- the anti-arthritic agents and/or analgesic agents of this invention can be administered to treat arthritis and/or alleviate pain by any means that produces contact of the active agent with the agent's site of action in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals; either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
- the dosage administered will, of course, vary depending upon known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.
- a daily dosage of active ingredient can be about 0.1 to 100 milligrams per kilogram of body weight.
- 0.2 to 50, and preferably 0.5 to 25 milligrams per kilogram per day given in divided doses 2 to 4 times a day or in sustained release form is effective to obtain desired results.
- Dosage forms (compositions) suitable for internal administration contain from about 1.0 milligrams to about 500 milligrams of active ingredient per unit.
- the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
- the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.
- Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
- powdered carriers such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the
- Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
- parenteral solutions In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
- Solutions for parenteral administration contain preferably a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
- Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid either alone or combined are suitable stabilizing agents.
- citric acid and its salts and sodium EDTA are also used.
- parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl or propyl paraben, and chlorobutanol.
- Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, E. W. Martin, a standard reference text in this field.
- Useful pharmaceutical dosage forms for administration of the compounds of this invention can be illustrated as follows:
- a large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 125 milligrams of lactose, 24 milligrams of talc, and 6 milligrams magnesium stearate.
- a mixture of active ingredient in soybean oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient.
- the capsules are washed in petroleum ether and dried.
- a large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 4 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of cornstarch and 98.8 milligrams of lactose.
- Appropriate coatings may be applied to increase palatability or delay absorption.
- a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water.
- the solution is made isotonic with sodium chloride and sterilized by commonly used techniques.
- An aqueous suspension is prepared for oral administration so that each 5 milliliters contain 100 milligrams of finely divided active ingredient, 200 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin.
- a procedure for detecting and comparing the antiinflammatory activity of compounds in this series and standard drugs for which there is a good correlation with human efficacy is the adjuvant-induced arthritis test in rats.
- test procedure employed for determining antiinflammatory activity is described below.
- mice Charles River Lewis male rats (130-150 grams) are injected subcutaneously in plantar area of the right hind paw with 0.1 ml of adjuvant (Difco heatkilled, lyophilized Mycobacterium butyricum suspended in mineral oil 5 mg/ml). 20 Non-arthritic controls are injected with mineral oil. The animals are held for 2 weeks to allow development of arthritis. Paw volumes (uninjected, left hind paw) are measured and the adjuvant injected rats are culled and distributed to treatment groups of 10 of equal disease severity. Non-arthritic controls are distributed to 2 groups of 10. The rats are given oral doses of compound or PVA-Acacia (Polyvinyl Alcohol 1%, Gum Acacia, U.S.P.
- Dose-response regression lines of the % decrease are plotted on semi-log paper by visual fit and the ED50% decrease from control paw volume is determined by inspection.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
TABLE I __________________________________________________________________________ ##STR12## Ex. No. R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.6 m.p. (°C.) __________________________________________________________________________ 1 CF.sub.3 CF.sub.3 4-CH.sub.3 Ophenyl 4-CH.sub.3 Ophenyl H 87-90° 2 CF.sub.3 CF.sub.3 4-Fphenyl 4-Fphenyl H 79-82° 3 CF.sub.3 CF.sub.3 4-Fphenyl 4-CH.sub.3 Sphenyl H 109-110° 4 CF.sub.3 CF.sub.3 4-Fphenyl 4-Clphenyl H 68-72° 5 CF.sub.3 CF.sub.3 phenyl phenyl H 65-67° 6 CF.sub.3 CF.sub.2 Cl 4-Fphenyl 4-Fphenyl H oil 7 CF.sub.3 CF.sub.2 H 4-Fphenyl 4-Fphenyl H oil 8 CF.sub.3 CF.sub.3 4-Fphenyl 4-(CH.sub.3).sub.2 Nphenyl H 9 CF.sub.3 CF.sub.2 H 4-Fphenyl 4-Brphenyl H 10 CF.sub.2 Cl CF.sub.2 Cl 4-Fphenyl 4-CH.sub.3 SOphenyl H 11 CF.sub.3 CF.sub.3 4-Fphenyl 4-CH.sub.3 SO.sub.2phenyl H 12 CF.sub.3 CF.sub.3 4-NO.sub.2phenyl 4-Fphenyl H 13 CF.sub.3 CF.sub.3 4-CH.sub.3phenyl 4-CH.sub.3phenyl H 82-83° 14 CF.sub.3 CF.sub.3 phenyl 3,4-Cl.sub.2phenyl H 15 CF.sub.2 Cl CClFH 4-Fphenyl 4-Fphenyl H 16 CF.sub.3 CCl.sub.2 H 4-Fphenyl 4-Fphenyl H 17 CF.sub.3 CFCl.sub.2 4-Fphenyl 4-Fphenyl H 18 CF.sub.3 CF.sub.3 2-Fphenyl 2-Fphenyl H oil 19 CF.sub.3 CF.sub.3 4-Fphenyl 2,4-F.sub.2phenyl H 20 CF.sub.3 CF.sub.3 4-Fphenyl 2,3-F.sub.2phenyl H 21 CF.sub.3 CF.sub.2 Cl 4-Fphenyl 2-F,3-Clphenyl H 22 CF.sub.3 CF.sub.3 4-Fphenyl 2-F,4-Clphenyl H 23 CF.sub.3 CF.sub.3 4-Fphenyl 4-Fphenyl CH.sub.3 24 CF.sub.3 CF.sub.3 4-Fphenyl 4-Fphenyl n-C.sub.3 H.sub.7 25 CF.sub.3 CF.sub.3 3-pyridyl 4-Fphenyl H 26 CF.sub.3 CF.sub.3 4-Fphenyl 2-pyridyl H 27 CF.sub.3 CF.sub.3 4-pyridyl 4-Fphenyl H __________________________________________________________________________
TABLE II ______________________________________ ##STR13## Ex. m.p. No.R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 (°C.) ______________________________________ 28CF.sub.3 CF.sub.3 4-Fphenyl 4-Fphenyl CH.sub.3 oil 29CF.sub.3 CF.sub.2 H 4-Fphenyl 4-Fphenyl CH.sub.3 30CF.sub.3 CF.sub.2 Cl 4-Fphenyl 4-Fphenyl CH.sub.3 31CF.sub.2 Cl CF.sub.2 Cl 4-Fphenyl 4-Fphenyl C.sub.2 H.sub.5 32CF.sub.3 CF.sub.3 phenyl phenyl C.sub.2 H.sub.5 33CF.sub.3 CF.sub.3 4-Fphenyl 4-Fphenyl n-C.sub.3 H.sub.7 34CF.sub.3 CF.sub.3 4-Fphenyl 4-Fphenyl i-C.sub.3 H.sub.7 ______________________________________
TABLE III ______________________________________ Daily Compound Oral Dose Percent Decrease From Example No. (mg/kg) Control Paw Volume ______________________________________ 1 27 47.sup.1 4 9 37.sup.3 13 24 27.sup.2 18 81 41.sup.1 ______________________________________ .sup.1 p < 0.001 compared to control by Students "t" test. .sup.2 p < 0.05 compared to control by Students "t" test. .sup.3 p < 0.1 compared to control by Students "t" test.
TABLE IV ______________________________________ Compound Example No. ED.sub.50.sup.4 (mg/kg) ______________________________________ 2 1.3 3 9 5 17 6 3.8 7 10.5 28 6.2 Indomethacin 0.25 Phenylbutazone 10 Aspirin 270 ______________________________________ .sup.4 ED.sub.50 = effective dose (mg/kg) for 50% decrease from control paw volume.
Claims (33)
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/316,661 US4427693A (en) | 1981-08-05 | 1981-11-02 | Antiinflammatory 4,5-diaryl-α,α-bis (polyhalomethyl)-2-thiophenemethanamines |
EP81110744A EP0055471A1 (en) | 1980-12-29 | 1981-12-23 | Antiinflammatory 4,5-diaryl-alpha,alpha-bis(polyhalomethyl)-2-thiophenemethanamines |
DK579181A DK579181A (en) | 1980-12-29 | 1981-12-28 | PROCEDURE FOR THE PREPARATION OF DIARYLTHIOPHENES |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US28899481A | 1981-08-05 | 1981-08-05 | |
US06/316,661 US4427693A (en) | 1981-08-05 | 1981-11-02 | Antiinflammatory 4,5-diaryl-α,α-bis (polyhalomethyl)-2-thiophenemethanamines |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US28899481A Continuation-In-Part | 1980-12-29 | 1981-08-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
US4427693A true US4427693A (en) | 1984-01-24 |
Family
ID=26965374
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US06/316,661 Expired - Fee Related US4427693A (en) | 1980-12-29 | 1981-11-02 | Antiinflammatory 4,5-diaryl-α,α-bis (polyhalomethyl)-2-thiophenemethanamines |
Country Status (1)
Country | Link |
---|---|
US (1) | US4427693A (en) |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994015932A1 (en) * | 1993-01-15 | 1994-07-21 | G.D. Searle & Co. | Novel 3,4-diaryl thiophenes and analogs thereof having use as antiinflammatory agents |
US5474995A (en) * | 1993-06-24 | 1995-12-12 | Merck Frosst Canada, Inc. | Phenyl heterocycles as cox-2 inhibitors |
US5691374A (en) * | 1995-05-18 | 1997-11-25 | Merck Frosst Canada Inc. | Diaryl-5-oxygenated-2-(5H) -furanones as COX-2 inhibitors |
US6432999B2 (en) | 1995-06-02 | 2002-08-13 | Pharmacia Corporation | Pyrazole substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
US6512121B2 (en) | 1998-09-14 | 2003-01-28 | G.D. Searle & Co. | Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
US6515014B2 (en) | 1995-06-02 | 2003-02-04 | G. D. Searle & Co. | Thiophene substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
US20030113402A1 (en) * | 2001-06-28 | 2003-06-19 | Howarth Jonathan N. | Microbiological control in animal processing |
US6599934B1 (en) | 1993-01-15 | 2003-07-29 | G.D. Searle & Co. | 3,4-diaryl thiopenes and analogs thereof having use as antiinflammatory agents |
US6613790B2 (en) | 2001-04-17 | 2003-09-02 | Pharmacia Corporation | Prodrugs of COX-2 inhibitors |
US6677364B2 (en) | 1998-04-20 | 2004-01-13 | G.D. Searle & Co. | Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
US20070286801A1 (en) * | 2002-04-15 | 2007-12-13 | The Regents Of The University Of California | Cyclooxygenase-2 selective agents useful as imaging probes and related methods |
WO2014160940A2 (en) * | 2013-03-29 | 2014-10-02 | Avoscience, Llc | Lipidic furan, pyrrole, and thiophene compounds for treatment of cancer, neurological disorders, and fibrotic disorders |
US10905673B2 (en) | 2016-04-27 | 2021-02-02 | Avoscience, Llc | Lipidic furan, pyrrole, and thiophene compounds for use in the treatment of atrophic vaginitis |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3644399A (en) | 1968-05-07 | 1972-02-22 | Wyeth John & Brother Ltd | Pyrrole lower alkanoic acids and derivatives |
US4174405A (en) | 1974-02-25 | 1979-11-13 | Uniroyal, Inc. | Thiophenes useful in control of acarids |
-
1981
- 1981-11-02 US US06/316,661 patent/US4427693A/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3644399A (en) | 1968-05-07 | 1972-02-22 | Wyeth John & Brother Ltd | Pyrrole lower alkanoic acids and derivatives |
US4174405A (en) | 1974-02-25 | 1979-11-13 | Uniroyal, Inc. | Thiophenes useful in control of acarids |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994015932A1 (en) * | 1993-01-15 | 1994-07-21 | G.D. Searle & Co. | Novel 3,4-diaryl thiophenes and analogs thereof having use as antiinflammatory agents |
US20030153602A1 (en) * | 1993-01-15 | 2003-08-14 | G.D. Searle & Co. | 3,4-diaryl thiophenes and analogs thereof having use as antiinflammatory agents |
US6599934B1 (en) | 1993-01-15 | 2003-07-29 | G.D. Searle & Co. | 3,4-diaryl thiopenes and analogs thereof having use as antiinflammatory agents |
US7030153B2 (en) | 1993-01-15 | 2006-04-18 | G.D. Searle & Co. | 3,4-diaryl thiophenes and analogs thereof having use as antiinflammatory agents |
US6239173B1 (en) | 1993-06-24 | 2001-05-29 | Merck Frosst Canada Inc./Merck Frosst Canada & Co. | 3-phenyl-4-(4(methylsulfonyl)phenyl)-2-(5H)-furanone as a cox-2 inhibitor |
US5474995A (en) * | 1993-06-24 | 1995-12-12 | Merck Frosst Canada, Inc. | Phenyl heterocycles as cox-2 inhibitors |
US5691374A (en) * | 1995-05-18 | 1997-11-25 | Merck Frosst Canada Inc. | Diaryl-5-oxygenated-2-(5H) -furanones as COX-2 inhibitors |
US6515014B2 (en) | 1995-06-02 | 2003-02-04 | G. D. Searle & Co. | Thiophene substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
US6432999B2 (en) | 1995-06-02 | 2002-08-13 | Pharmacia Corporation | Pyrazole substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
US6753344B2 (en) | 1995-06-02 | 2004-06-22 | Pharmacia Corporation | Thiophene substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
US6875785B2 (en) | 1995-06-02 | 2005-04-05 | Pharmacia Corporation | Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
US6998415B2 (en) | 1996-05-31 | 2006-02-14 | Pharmacia Corporation | Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
US6677364B2 (en) | 1998-04-20 | 2004-01-13 | G.D. Searle & Co. | Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
US6512121B2 (en) | 1998-09-14 | 2003-01-28 | G.D. Searle & Co. | Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
US6613790B2 (en) | 2001-04-17 | 2003-09-02 | Pharmacia Corporation | Prodrugs of COX-2 inhibitors |
US20030113402A1 (en) * | 2001-06-28 | 2003-06-19 | Howarth Jonathan N. | Microbiological control in animal processing |
US20070286801A1 (en) * | 2002-04-15 | 2007-12-13 | The Regents Of The University Of California | Cyclooxygenase-2 selective agents useful as imaging probes and related methods |
US7329401B2 (en) | 2002-04-15 | 2008-02-12 | The Regents Of The University Of California | Cyclooxygenase-2 selective agents useful as imaging probes and related methods |
WO2014160940A2 (en) * | 2013-03-29 | 2014-10-02 | Avoscience, Llc | Lipidic furan, pyrrole, and thiophene compounds for treatment of cancer, neurological disorders, and fibrotic disorders |
WO2014160940A3 (en) * | 2013-03-29 | 2014-12-31 | Avoscience, Llc | Lipidic furan, pyrrole, and thiophene compounds for treatment of cancer, neurological disorders, and fibrotic disorders |
US9371302B2 (en) | 2013-03-29 | 2016-06-21 | Avoscience, Llc | Lipidic furan, pyrrole, and thiophene compounds for treatment of cancer |
US9814694B2 (en) | 2013-03-29 | 2017-11-14 | Avioscience, LLC | Lipidic furan, pyrrole, and thiophene compounds for treatment of cancer, neurological disorders, and fibrotic disorders |
US10085962B2 (en) | 2013-03-29 | 2018-10-02 | Avoscience, Llc | Lipidic furan, pyrrole, and thiophene compounds for treatment of cancer, neurological disorders, and fibrotic disorders |
US10525031B2 (en) | 2013-03-29 | 2020-01-07 | Avoscience, Llc | Lipid furan, pyrrole, and thiophene compounds for treatment of cancer, neurological disorders, and fibrotic disorders |
US11058663B2 (en) | 2013-03-29 | 2021-07-13 | Avoscience, Llc | Lipidic furan, pyrrole, and thiophene compounds for treatment of cancer, neurological disorders, and fibrotic disorders |
US11833129B2 (en) | 2013-03-29 | 2023-12-05 | Avoscience, Llc | Thiophene compound for treatment of exfoliating glaucoma |
US10905673B2 (en) | 2016-04-27 | 2021-02-02 | Avoscience, Llc | Lipidic furan, pyrrole, and thiophene compounds for use in the treatment of atrophic vaginitis |
US11602518B2 (en) | 2016-04-27 | 2023-03-14 | Avoscience, Llc | Lipidic furan, pyrrole, and thiophene compounds for use in the treatment of atrophic vaginitis |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4381311A (en) | Antiinflammatory 4,5-diaryl-α-(polyhalomethyl)-2-thiophenemethanols | |
US4503065A (en) | Antiinflammatory 4,5-diaryl 1-2-halo imidazoles | |
EP0008755B1 (en) | Antiinflammatory 4,5-diaryl-2-nitroimidazoles, method for their preparation and pharmaceutical composition containing them | |
US4302461A (en) | Antiinflammatory 5-substituted-2,3-diarylthiophenes | |
US4427693A (en) | Antiinflammatory 4,5-diaryl-α,α-bis (polyhalomethyl)-2-thiophenemethanamines | |
EP0034798B1 (en) | Antiinflammatory 4,5-diaryl-2-(substituted-thio)pyrroles and their corresponding sulfoxides and sulfones | |
US4438117A (en) | 2-Substituted thio-4,5-diarylpyrimidines | |
US4348404A (en) | Antiinflammatory 4,5-diaryl-α-polyfluoroalkyl-1H-imidazole-2-methanamines | |
US4432974A (en) | Antiinflammatory and/or analgesic 2,3-diaryl-5-silyl thiophenes | |
US4652582A (en) | Antiinflammatory-2-halo-4,5-diarylpyrroles | |
EP0087629B1 (en) | Antiinflammatory and/or analgesic 2,3-diaryl-5-halo thiophenes | |
US4372964A (en) | Antiinflammatory 4,5-diaryl-1H-imidazole-2-methanols | |
US4590205A (en) | Antiinflammatory and/or analgesic 2,3-diaryl-5-halo thiophenes | |
US4267190A (en) | Antiinflammatory 4,5-diaryl-α,α-bis(polyfluoromethyl)-1H-pyrrole-2-methanethiols | |
US4820827A (en) | 2,3-diaryl-5-bromothiophene compounds of use for the treatment of inflammaton and dysmenorrhea | |
US4927835A (en) | Acylphenol derivatives, useful as anti-inflammatory agents and pain suppressants | |
EP0038536B1 (en) | Antiinflammatory 4,5-diaryl-alpha-(polyfluoroalkyl)-1h-pyrrole-2-methanamines | |
EP0055471A1 (en) | Antiinflammatory 4,5-diaryl-alpha,alpha-bis(polyhalomethyl)-2-thiophenemethanamines | |
US4749712A (en) | Antiinflammatory and/or analgesic 5-alkylthiophenes | |
US4477463A (en) | Antiinflammatory and/or analgesic 1-alkyl-4,5-diaryl-2-fluoroalkyl-1H-pyrroles | |
US4330552A (en) | Antiinflammatory 4,5-diaryl-2-arylthioimidazoles | |
US5124334A (en) | Benzylalcohol phospholipase A2 inhibitors | |
US4500520A (en) | Antiinflammatory and/or analgesic silylfurans | |
US4318917A (en) | Antiinflammatory 2,3-diaryl-5-[2,2,2-trifluoro-1-(trifluoromethyl]ethyl-1H-pyrroles | |
US3818092A (en) | Pyridyl ketipate lactones and derivatives in treating arthritis |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: E.I. DU PONT DE NEMOURS AND COMPANY WILMINGTON, DE Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:HABER, STEPHEN B.;REEL/FRAME:004186/0580 Effective date: 19811028 |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, PL 96-517 (ORIGINAL EVENT CODE: M170); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY Year of fee payment: 4 |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YEAR, PL 96-517 (ORIGINAL EVENT CODE: M171); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY Year of fee payment: 8 |
|
AS | Assignment |
Owner name: DU PONT MERCK PHARMACEUTICAL COMPANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:E.I. DU PONT DE NEMOURS AND COMPANY;REEL/FRAME:005955/0010 Effective date: 19910426 |
|
FEPP | Fee payment procedure |
Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
LAPS | Lapse for failure to pay maintenance fees | ||
FP | Lapsed due to failure to pay maintenance fee |
Effective date: 19960121 |
|
STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |